Expert Consensus on Prevention and Treatment of Aging-Related Gonadal Dysfunction.

Aging-related hypogonadism involves complex mechanisms in humans, predominantly relating to the decline of multiple hormones and senile gonads. Late-onset hypogonadism (LOH) and erectile dysfunction (ED) are the main manifestations in men, while premature ovarian insufficiency (POI) and menopause are the main forms in women. Anti-aging measures include lifestyle modification and resistance training, hormonal supplementation, stem cell therapy, metformin, and rapamycin. In this expert consensus, the mechanisms, efficacy, and side effects of stem cell therapy on aging gonadal function are reviewed. Furthermore, various methods of stem cell therapy, administered intravenously, intracavernously, and intra-ovarially, are exemplified in detail. More clinical trials on aging-related gonadal dysfunction are required to solidify the foundation of this topic.

Age-Related Dysfunction in Balance: A Comprehensive Review of Causes, Consequences, and Interventions.

This review delves into the multifaceted aspects of age-related balance changes, highlighting their prevalence, underlying causes, and the impact they have on the elderly population. Central to this discussion is the exploration of various physiological changes that occur with aging, such as alterations in the vestibular, visual, proprioceptive systems, and musculoskeletal degeneration. We examine the role of neurological disorders, cognitive decline, and medication side effects in exacerbating balance issues. The review underscores the significance of early detection and effective intervention strategies in mitigating the risks associated with balance problems, such as falls and reduced mobility. It discusses the effectiveness of diverse intervention strategies, including exercise programs, rehabilitation techniques, and technological advancements like virtual reality, wearable devices, and telemedicine. Additionally, the review stresses the importance of a holistic approach in managing balance disorders, encompassing medication review, addressing comorbidities, and environmental modifications. The paper also presents future research directions, emphasizing the need for a deeper understanding of the complex mechanisms underlying balance changes with aging and the potential of emerging technologies and interdisciplinary approaches in enhancing assessment and intervention methods. This comprehensive review aims to provide valuable insights for healthcare providers, researchers, and policymakers in developing targeted strategies to improve the quality of life and ensure the well-being of the aging population.

Cerebellum and Aging: Update and Challenges.

The cerebellum plays a vital role in the aging process. With the aging of the cerebellum, there is a decline in balance and motor function, particularly fine motor skills, and an increased risk of falling. However, in recent years, numerous studies have revealed that the cerebellum has several roles beyond balance and fine motor skills, such as cognitive function and memory. It also plays a role in many neurodegenerative diseases. Interestingly, the cerebellum ages more rapidly than other brain regions, including the hippocampus. With increasing studies reporting that the cerebellum has a more prominent and interconnected role in the brain, it is essential to understand why aging affects it more, leading to solutions to help curb the accelerated decline. Here, we summarize the cerebellum's function and look at how it ages at the cellular, molecular, and functional levels. Additionally, we explore the the effects of alcoholism on the aging cerebellum as well as the role of the cerebellum in diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis.

Hypoxic Conditioning: A Potential Perioperative Strategy to Reduce Abdominal Aortic Occlusion-Related Injury in Mouse Proximal and Distal Organs.

This study aimed to investigate the impact of abdominal aortic occlusion (AAO)- induced injury on the kidney, lower limb muscles, heart, and brain in mice, and the potential protective effects of hypoxic postconditioning (HyC). The experimental design employed an abdominal aortic occlusion (AAO) model, and involved three groups of mice: sham, AAO, and AAO+HyC. Ten minutes after the AAO model, mice were subjected to hypoxic treatment lowering oxygen concentration to 5% within 45 minutes, and then returned to a normal oxygen environment. Hematoxylin- eosin (HE) stain was used for Histopathological examinations, and Quantibody Mouse Array was used for detecting apoptosis and inflammation-related protein expression. Histopathological examinations showed that HyC mitigated pathological damage to proximal organs (kidneys and lower limb muscles), distal organs (heart and brain), and reduced inflammatory cell infiltration. Expression of apoptosis- and inflammation-related proteins in brain and heart tissues were also evaluated. HyC significantly increased cellular inhibitor of apoptosis 2 (cIAP2) in the brain and Bcl-2 and insulin-like growth factor 2 (IGF-2) in the heart. Additionally, HyC regulated the expression of several inflammation-related factors in both brain and heart tissues. Although further investigation is needed, particularly in human subjects, this study highlights the potential of HyC as a promising therapeutic strategy for reducing AAO-associated organ damage.

Combination of Atractylenolide I, Atractylenolide III, and Paeoniflorin promotes angiogenesis and improves neurological recovery in a mouse model of ischemic Stroke.

BACKGROUND: Prognosis is critically important in stroke cases, with angiogenesis playing a key role in determining outcomes. This study aimed to investigate the potential protective effects of Atractylenolide I (Atr I), Atractylenolide III (Atr III), and Paeoniflorin (Pae) in promoting angiogenesis following cerebral ischemia. METHODS: The bEnd.3 cell line was used to evaluate the effects of these three compounds on vascular endothelial cell proliferation, migration, and tube formation. Male C57BL/6 mice underwent transient middle cerebral artery occlusion (MCAO), followed by daily intragastric administration of the Chinese medicine compounds to assess their impact on brain protection and angiogenesis. In vivo experiments included measuring infarct size and assessing neurological function. Immunofluorescence staining and an angiogenesis antibody array were used to evaluate angiogenesis in ischemic brain tissue. Functional enrichment analysis was performed to further investigate the pathways involved in the protective effects of the compounds. Molecular docking analysis explored the potential binding affinity of the compounds to insulin-like growth factor 2 (IGF-2), and Western blotting was used to measure levels of angiogenesis-related proteins. RESULTS: In vitro, the combination of Atr I, Atr III, and Pae enhanced cell proliferation, promoted migration, and stimulated tube formation. In vivo, the combined treatment significantly facilitated neurological function recovery and angiogenesis by day 14. The treatment also increased levels of angiogenesis-related proteins, including IGF-2. Pearson correlation analysis revealed a strong positive association between IGF-2 levels in ischemic brain tissue and angiogenesis, suggesting a good affinity of the compounds for the IGF-2 binding site, as supported by molecular docking analysis. CONCLUSION: The administration of Atr I, Atr III, and Pae has shown significant enhancements in long-term stroke recovery in mice, likely due to the promotion of angiogenesis via increased activation of the IGF-2 pathway in ischemic brain tissue.

Hypoxic postconditioning drives protective microglial responses and ameliorates white matter injury after ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is a cerebrovascular disease with high incidence and mortality. White matter repair plays an important role in the long-term recovery of neurological function after cerebral ischemia. Neuroprotective microglial responses can promote white matter repair and protect ischemic brain tissue. AIMS: The aim of this study was to investigate whether hypoxic postconditioning (HPC) can promote white matter repair after IS, and the role and mechanism of microglial polarization in white matter repair after HPC treatment. MATERIALS & METHODS: Adult male C57/BL6 mice were randomly divided into three groups: Sham group (Sham), MCAO group (MCAO), and hypoxic postconditioning group (HPC). HPC group were subjected to 45 min of transient middle cerebral artery occlusion (MCAO) immediately followed by 40 min of HPC. RESULTS: The results showed that HPC reduced the proinflammatory level of immune cells. Furthermore, HPC promoted the transformation of microglia to anti-inflammatory phenotype on the third day after the procedure. HPC promoted the proliferation of oligodendrocyte progenitors and increased the expression of myelination-related proteins on the 14th day. On the 28th day, HPC increased the expression of mature oligodendrocytes, which enhanced myelination. At the same time, the motor neurological function of mice was restored. DISCUSSION: During the acute phase of cerebral ischemia, the function of proinflammatory immune cells was enhanced, long-term white matter damage was aggravated, and motor sensory function was decreased. CONCLUSION: HPC promotes protective microglial responses and white matter repair after MCAO, which may be related to the proliferation and differentiation of oligodendrocytes.

Pericyte Dysfunction Contributes to Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats.

Vascular cognitive impairment (VCI) encompasses cognitive disorders associated with cerebrovascular disease, often manifesting as white matter lesions (WMLs), irrespective of precise triggers. The integrity of white matter is essential for neural communication and cognitive function maintenance. Persistent cerebral hypoperfusion-induced WMLs are now acknowledged as a key driver of VCI and dementia, though their exact formation mechanism remains unclear. Recent studies link pericyte dysfunction to diverse brain disorders like Alzheimer disease. However, the exact pathological connection between pericyte dysfunction and cognitive impairment in VCI remains unexplored. In this study, we aimed to examine whether pericyte dysfunction could impact WMLs and cognitive impairment in a rat VCI model. Using a rat model of chronic cerebral hypoperfusion-induced VCI through two-vessel occlusion (2VO), we verified that 2VO induced both WMLs and cognitive impairment. Notably, the number of pericytes in the brain was significantly altered after 2VO. Furthermore, we observed significantly increased capillary constrictions at pericyte bodies in the brains of 2VO-induced rats compared to sham-operated rats, accompanied by reduced cerebral blood flow (CBF). To tackle this issue, we administered CGS21680, a specific adenosine A2A subtype receptor agonist, intranasally twice a day for 7 days. We found that rats treated with CGS21680 exhibited a significant increase in CBF at 7 and 14 days after 2VO, compared to the vehicle group. Moreover, capillary lumens beneath pericytes also increased after the CGS21680 treatment. Importantly, the treatment led to substantial improvements in WMLs and cognitive impairment compared to the vehicle group. Our findings suggest a critical role of pericyte dysfunction in WMLs and cognitive impairment within the rat VCI model. This insight contributes to our understanding of pathogenesis and offers prospects for targeted intervention in VCI.

NeuroD4 converts glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 antioxidant axis.

Cell fate and proliferation ability can be transformed through reprogramming technology. Reprogramming glioblastoma cells into neuron-like cells holds great promise for glioblastoma treatment, as it induces their terminal differentiation. NeuroD4 (Neuronal Differentiation 4) is a crucial transcription factor in neuronal development and has the potential to convert astrocytes into functional neurons. In this study, we exclusively employed NeuroD4 to reprogram glioblastoma cells into neuron-like cells. In vivo, the reprogrammed glioblastoma cells demonstrated terminal differentiation, inhibited proliferation, and exited the cell cycle. Additionally, NeuroD4 virus-infected xenografts exhibited smaller sizes compared to the GFP group, and tumor-bearing mice in the GFP+NeuroD4 group experienced prolonged survival. Mechanistically, NeuroD4 overexpression significantly reduced the expression of SLC7A11 and Glutathione peroxidase 4 (GPX4). The ferroptosis inhibitor ferrostatin-1 effectively blocked the NeuroD4-mediated process of neuron reprogramming in glioblastoma. To summarize, our study demonstrates that NeuroD4 overexpression can reprogram glioblastoma cells into neuron-like cells through the SLC7A11-GSH-GPX4 signaling pathway, thus offering a potential novel therapeutic approach for glioblastoma.

Remote ischemic conditioning alleviates chronic cerebral hypoperfusion-induced cognitive decline and synaptic dysfunction via the miR-218a-5p/SHANK2 pathway.

Vascular cognitive impairment (VCI) due to chronic cerebral hypoperfusion (CCH), is the second leading cause of dementia. Although synaptic impairment plays a critical role in VCI, its exact mechanism remains unknown. Our previous research revealed that remote ischemic conditioning (RIC) could alleviate cognitive decline resulting from CCH, however, its effects on synaptic impairment remain unclear. In this study, we confirmed that RIC alleviated both cognitive decline and its associated synaptic dysfunction caused by CCH. RNA sequencing revealed that CCH increased in miR-218a-5p expression, which was decreased by RIC. Elevated miR-218a-5p levels limited the benefits of RIC, however, inhibiting miR-218a-5p in hippocampal CA1 neurons rescued synaptic dysfunction. Additionally, we found that SHANK2 is a downstream target of miR-218a-5p, and inhibiting SHANK2 expression reduced the alleviation caused by hypoxic conditioning in synaptic impairment in vitro. In conclusion, our results suggested that RIC alleviated synaptic impairment via the miR-218a-5p/SHANK2 pathway, which could be a potential biomarker or therapeutic target for cognitive impairment caused by CCH.

Mitochondria and Neurodegenerative Diseases: A New Hotspot.

Growing evidence suggests that the prevalence of neurodegenerative diseases (NDs) is on the rise with the aged population with substantially overlapping clinical and pathological features. The journal "Aging & Disease" portals are always responsive to publishing cutting-edge research on age-related neurodegeneration. Even though outstanding progress has recently been made in understanding NDs, the underlying mechanisms involved in neuronal degeneration are yet to be deciphered and addressed. There is credible evidence showing multiple links between mitochondria and NDs, gradually becoming the hotspot in mechanistic or drug development research. The editorial aims to reflect on and discuss some interesting and unique results from the papers published in "Aging & Disease" during the past three years (2020 - 2022).

Aging During the Pandemic: Untangling the Complexities of COVID-19 and Geriatric Care.

The COVID-19 pandemic has posed unprecedented challenges to the global healthcare system, with the elderly population being particularly vulnerable. This comprehensive review synthesizes the findings from publications in "Aging and Disease", highlighting the unique challenges older adults encountered during the pandemic and providing solutions thereof. These studies provide invaluable insights into the elderly population's vulnerabilities and needs during the COVID-19 pandemic. The susceptibility to the virus in older individuals remains debatable, and research on the clinical picture of COVID-19 in older populations has yielded insights into clinical features, molecular mechanisms, and potential therapeutic strategies. This review intends to shed light on the need of sustaining physical and mental well-being among older adults during the periods of lockdown by extensively exploring these concerns and emphasizing the need for targeted interventions and support systems for this population. Ultimately, the findings of these studies contribute to developing more effective and comprehensive approaches to managing and mitigating the risks posed by the pandemic to the elderly.

Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway.

Increasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.

QEEG Signatures are Associated with Nonmotor Dysfunctions in Parkinson's Disease and Atypical Parkinsonism: An Integrative Analysis.

Parkinson's disease (PD) and atypical parkinsonism (AP), including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), share similar nonmotor symptoms. Quantitative electroencephalography (QEEG) can be used to examine the nonmotor symptoms. This study aimed to characterize the patterns of QEEG and functional connectivity (FC) that differentiate PD from PSP or MSA, and explore the correlation between the differential QEEG indices and nonmotor dysfunctions in PD and AP. We enrolled 52 patients with PD, 31 with MSA, 22 with PSP, and 50 age-matched health controls to compare QEEG indices among specific brain regions. One-way analysis of variance was applied to assess QEEG indices between groups; Spearman's correlations were used to examine the relationship between QEEG indices and nonmotor symptoms scale (NMSS) and mini-mental state examination (MMSE). FCs using weighted phase lag index were compared between patients with PD and those with MSA/PSP. Patients with PSP revealed higher scores on the NMSS and lower MMSE scores than those with PD and MSA, with similar disease duration. The delta and theta powers revealed a significant increase in PSP, followed by PD and MSA. Patients with PD presented a significantly lower slow-to-fast ratio than those with PSP in the frontal region, while patients with PD presented significantly higher EEG-slowing indices than patients with MSA. The frontal slow-to-fast ratio showed a negative correlation with MMSE scores in patients with PD and PSP, and a positive correlation with NMSS in the perception and mood domain in patients with PSP but not in those with PD. Compared to PD, MSA presented enhanced FC in theta and delta bands in the posterior region, while PSP revealed decreased FC in the delta band within the frontal-temporal cortex. These findings suggest that QEEG might be a useful tool for evaluating the nonmotor dysfunctions in PD and AP. Our QEEG results suggested that with similar disease duration, the cortical neurodegenerative process was likely exacerbated in patients with PSP, followed by those with PD, and lastly in patients with MSA.

A Reliable Nonhuman Primate Model of Ischemic Stroke with Reproducible Infarct Size and Long-term Sensorimotor Deficits.

A nonhuman primate model of ischemic stroke is considered as an ideal preclinical model to replicate various aspects of human stroke because of their similarity to humans in genetics, neuroanatomy, physiology, and immunology. However, it remains challenging to produce a reliable and reproducible stroke model in nonhuman primates due to high mortality and variable outcomes. Here, we developed a focal cerebral ischemic model induced by topical application of 50% ferric chloride (FeCl3) onto the MCA-M1 segment through a cranial window in the cynomolgus monkeys. We found that FeCl3 rapidly produced a stable intraarterial thrombus that caused complete occlusion of the MCA, leading to the quick decrease of the regional cerebral blood flow in 10 min. A typical cortical infarct was detected 24 hours by magnetic resonance imaging (MRI) and was stable at least for 1 month after surgery. The sensorimotor deficit assessed by nonhuman primate stroke scale was observed at 1 day and up to 3 months after ischemic stroke. No spontaneous revascularization or autolysis of thrombus was observed, and vital signs were not affected. All operated cynomolgus monkeys survived. Our data suggested that FeCl3-induced stroke in nonhuman primates was a replicable and reliable model that is necessary for the correct prediction of the relevance of experimental therapeutic approaches in human beings.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis.

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32/MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelin/myelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP+/Iba1+/CD68+ microglia was significantly reduced in the BCCAO rats pretreated with these three drugs compared with the vehicle group, suggesting that these drugs suppress microglial phagocytosis. No significant difference was found between the groups pretreated with metformin, rapamycin, or NMN. Our data suggest that metformin, rapamycin, or NMN could protect or attenuate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings may open a new avenue for VCI treatment.

Transplantation of Roxadustat-preconditioned bone marrow stromal cells improves neurological function recovery through enhancing grafted cell survival in ischemic stroke rats.

AIMS: The therapeutic effect of bone marrow stromal cell (BMSC) transplantation for ischemic stroke is limited by its low survival rate. The purpose of this study was to evaluate whether Roxadustat (FG-4592) pretreatment could promote the survival rate of grafted BMSCs and improve neurological function deficits in ischemia rats. METHODS: Oxygen-glucose deprivation (OGD) and permanent middle cerebral artery occlusion (pMCAO) were constructed as stroke models in vitro and in vivo. Flow cytometry analysis and expression of Bax and Bcl-2 were detected to evaluate BMSCs apoptosis. Infarct volume and neurobehavioral score were applied to evaluate functional recovery. Inflammatory cytokine expression, neuronal apoptosis, and microglial M1 polarization were assessed to confirm the enhanced neurological recovery after FG-4592 pretreatment. RESULTS: FG-4592 promoted autophagy level to inhibit OGD-induced apoptosis through HIF-1α/BNIP3 pathway. GFP and Ki67 double staining showed an improved survival rate of BMSCs in the FG-4592 group, whereas infarct volume and neurobehavioral score verified its enhanced neurological recovery activity simultaneously. NeuN and Iba-1 fluorescence staining showed improved neural survival and decreased microglial activation, along with decreased IL-1ß, IL-6, and TNF-α levels through the TLR-4/NF-kB pathway. CONCLUSIONS: FG-4592 pretreated BMSCs improve neurological function recovery after stroke and are likely to be a promising strategy for stroke management.

Cerebral small vessel disease alters neurovascular unit regulation of microcirculation integrity involved in vascular cognitive impairment.

Cerebral small vessel disease (CSVD) is a generic term used for intracranial vascular disorders caused by the structural changes of cerebral microvessels, including the small arteries, arterioles, capillaries and venules. CSVD exhibits various neuroimaging features and is associated clinical characteristics. Although CSVD is recognized as the leading cause of vascular cognitive impairment (VCI), the underlying mechanism(s) remains elusive. Growing evidence indicates a significant association between altered neurovascular unit (NVU) functioning and the pathophysiology of evolving CSVD-induced VCI. Therefore, research is required to understand how NVU dysregulation contributes to cognitive impairment due to CSVD. In this review, we describe the link between the neuroimaging focal lesions and cognitive alterations. We also discuss the potential pathological role of NVU dysregulation in the entry of pathogens from the blood into the parenchyma by altering the blood-brain barrier (BBB), affecting the cerebral microvascular and consequently cause VCI. Next, we review the coupling of neural activity with cerebral blood flow to control the microvascular perfusion; and the disrupted clearance of metabolic byproducts with CSF-ISF exchange via perivascular pathways and glymphatic system. Finally, we discussed the possible therapeutic interventions in CSVD.

Nonhuman primate models of ischemic stroke and neurological evaluation after stroke.

Nonhuman primates are closer to human beings than rodents in genetics, neuroanatomy, physiology and immunology. Nonhuman primates are therefore considered an ideal preclinical model to replicate various aspects of human stroke. Ischemia stroke models in nonhuman primates can better fit the physiological symptoms and changes in humans after cerebral ischemia. Currently, various construction methods and neurological evaluation methods have been developed and applied to stroke models of nonhuman primates, including craniectomy models, endovascular stroke models, autologous thrombus models and intraluminal filament models. Meanwhile, new innovative methods have emerged, such as the endothelin-1 model and photothrombosis model. In the past thirty years, these model studies have explored various mechanisms that are initiated in the first minutes, hours, and days after a stroke. Permanent and temporary middle cerebral artery occlusion models have been trying to simulate the complex situation of human stroke. However, a comprehensive comparison of the above methods, including their advantages and disadvantages, difficulty and application fields, is limited. Here, we introduce various modeling methods that are currently available for nonhuman primate stroke models, compare the differences between these different preparation methods, and analyze the advantages and disadvantages of the various methods and the fields of application. The imaging detection methods of nonhuman primates after cerebral ischemia and the neurological evaluation methods after stroke are also discussed briefly. Methods are sorted and compared so that scholars can choose appropriate modeling methods and evaluation methods to establish nonhuman primate stroke models.